Central Sympathetic Regulation of Thermogenesis in Fever

描述(申请人提供)：发烧是一种防御性的体温升高，在感染期间释放的一连串内源性热原刺激的急性时相反应中发挥重要作用。体温的高热是由中枢神经系统协调的自主神经和躯体运动反应的结果，该反应是在大脑中主要的体温调节整合中心-视前区(POA)产生的热源性介质前列腺素E2(PGE2)的增加。PGE2与POA神经元上的EP3抑制受体结合，通过激活四个主要体温调节效应器的神经通路来增加核心体温：棕色脂肪组织(BAT)产热增加，骨骼肌颤抖和明显的心动过速产生的热增加，以及通过皮肤血管收缩(CVC)增加热保存。同样的一系列反应：到蝙蝠、到心脏和到皮肤血管的交感神经外流增加，以及到肌肉的躯体运动神经元放电增加，也构成了对皮肤冷感受器的刺激或核心温度下降的冷防御稳态反射反应。在之前的资助期间，我们在了解体温调节通路中调节活动的功能组织和神经递质方面取得了重大进展，这些通路介导了蝙蝠产热、心率和CVC的增加，从而导致了POA对PGE2的发热反应和对皮肤降温的寒冷防御反应。我们建议通过使用我们在过去几年中完善的富有成效的体内电生理、解剖学和神经药理学方法来扩展这些研究，以解决三个具体目标，这将为影响发热的大脑机制和执行体温调节的关键动态平衡功能提供新的和重要的见解。第一个目的将通过确定PGE2和冷诱发的颤抖反应的中枢神经机制来验证躯体以及交感的冷热防御反应是通过POA和延髓中缝之间的分层通路来组织的假设。第二个目标将确定调节皮肤血液流动的体温调节网络和驱动蝙蝠产热的体温调节网络之间性能根本差异的神经基础。第三个目标将集中在温度调节中的关键整合神经元：POA的输出神经元，以了解温度调节效应器的差异控制机制，并确定它们在调节热失调条件下对神经递质系统的效应反应中的作用。公共卫生相关性：了解调节发热和寒冷防御的中枢神经机制，对于开发治疗方法来对抗危及生命的过度发热(如败血症、毒血症、脑膜炎和一些癌症)，以及管理在各种其他临床重要情况下发生的热失调的影响，如脑缺血和中风，苯丙胺类药物的滥用，更年期和前列腺手术时的潮热，以及手术麻醉期间引起的体温过低，都是相关的。

Description (provided by applicant): Fever is a defended elevation in body temperature that plays a significant role in the acute phase reaction stimulated by a cascade of endogenous pyrogens released during infection. The febrile increase in body temperature is the result of a patterned autonomic and somatic motor response orchestrated by the central nervous system in response to an increased production of the pyrogenic mediator, prostaglandin E2 (PGE2), in the preoptic area (POA), a principal thermoregulatory integration center in the brain. PGE2 binding to EP3 inhibitory receptors on neurons in the POA increases core body temperature by activating neural pathways to four principal thermoregulatory effectors: increased heat production from brown adipose tissue (BAT) thermogenesis, from shivering in skeletal muscle and from a marked tachycardia and increased heat conservation through cutaneous vasoconstriction (CVC). This same constellation of responses: augmented sympathetic outflows to BAT, to the heart and to skin blood vessels and increased somatic motorneuron discharge to muscle, also constitutes the cold defense homeostatic reflex response to stimulation of cutaneous cold receptors or falls in core temperature. In the previous funding period, we have made significant progress in understanding the functional organization and neurotransmitters regulating the activity in the thermoregulatory pathways mediating the increases in BAT thermogenesis, heart rate and CVC contributing to the febrile response to PGE2 in the POA and to cold defense responses to skin cooling. We propose to extend these studies by using the fruitful in vivo electrophysiological, anatomical and neuropharmacological approaches we have perfected over the past several years to address three specific aims that will provide new and important insights into the brain mechanisms effecting fever and performing the critical homeostatic function of thermoregulation. The first aim will test the hypothesis that somatic, as well as sympathetic febrile and cold defense responses are organized through a hierarchical pathway between the POA and the medullary raphe by determining the central neural mechanism underlying the PGE2- and cold-evoked shivering response. The second aim will determine the neural basis for the fundamental differences in performance between the thermoregulatory network regulating skin blood flow and that driving BAT thermogenesis. The third aim will focus on the key integrative neurons in thermoregulation: the output neurons of the POA, to understand the mechanism for the differential control of thermoregulatory effectors and to determine their role in mediating effector responses to neurotransmitter systems implicated in conditions of thermal dysregulation. PUBLIC HEALTH RELEVANCE: Understanding the central neural mechanisms mediating fever and cold defense is relevant to the development of therapeutic approaches to combat life-threatening excessive fevers (as during sepsis, toxemia, meningitis, some cancers) and to the management of the effects of thermal dysregulation that occurs during a variety of other clinically significant conditions such as cerebral ischemia and stroke, the abuse of amphetamine-based drugs, the hot flashes accompanying menopause and prostate surgery and the hypothermia induced during surgical anesthesia.